Insufficient copper (Cu) during perinatal development of rodents has a major impact on the central nervous system leading to altered neurochemistry and behavior even after long-term Cu repletion. Human intakes of Cu during pregnancy and lactation may be suboptimal but current RDA recommendations do not encourage the need for supplements. The long-range goal of this research is to identify the biochemical roles of Cu responsible for severe long-term neurochemical and behavioral consequences of perinatal Cu deficiency. Four specific aims will test the overall hypothesis that altered cuproenzymes are responsible for the phenotype observed. Research will utilize nutritional and genetic models with Holtzman rats and transgenic mice. AIM 1: We will test the hypothesis that limitation in the Cu-dependent enzyme dopamine beta- monooxygenase (DBM) is responsible by treating rats with L-3.4-dihydroxyphenvlserine (L-DOPS) to bypass the DBM step and restore low brain norepinephrine. AIM 2: We will test the hypothesis that limitation in Cu.Zn-superoxide dismutase (SOD) is responsible by comparing features of Cu deficiency in SOD -/- mice to wild-type controls Secondly, we will compare these mice to mice with altered SOD activity, Ctrl +/- mice, due to lower copper transport capacity. Thirdly, we will restore the deficit in SOD activity following these treatments with TEMPOL a membrane permeable SOD mimetic. AIM 3: We will test the hypothesis that limitation in mitochondrial cytochrome C oxidase (CCO) is responsible by characterizing brain energy metabolism in Cu deficient rats with a rat model of chronic CCO inhibition that uses cyanide. AIM 4: We will test the hypothesis that limitation in Cu-dependent ferroxidases lead to lower brain iron and are responsible by comparing rats reared on an iron-fortified diet to restore brain iron.